New 16-substituted 1, 3, 5(10)-estratrienes



United States Patent Wee 3,091,609 NEW 16-SUBSTITUTED 1,3,5()-ESTRATRIENES Robert E. Sehaub, Paramus, and Martin J. Weiss, Oradell, N.J., assignors to American Cyanamid Company, New York, N.Y., a corporation of Maine No Drawing. Filed Dec. 20, 1961, Ser. No. 160,951 6 Claims. (Cl. 260239.5)

This invention relates to new steroids of the estrone series. More particularly, it relates to 3-lower alkoxy- 17-oxo-l,3,5 l0)-estratrienes.

The novel steroids of the present invention may be illustrated by the following structural formula:

where R is a lower alkyl radical and R is a radical selected from the group consisting of lower alkylthio, halogen, amino, lower alkylamino, dilower alkylamino, lower alkoxyamino, cycloalkylamino, mononuclear aryl amino, pyridylamino, pentamethyleneimino, oxapentamethyleneimino, dilower alkylamino lower alkylarnino, lower alkyl halide salts and mineral acid addition salts thereof, l-(2-pyridyl)piperazinyl, 3-lower alkoxy-l7-oxo- 1,3,5 (l0)-estratriene l6 ylidenemethylthio and N-[3- lower alkoxy-17-oxo-1,3,5(l0)-estratrien 16 ylidenemethyl] azapentamethyleneimino radicals.

In the compounds of the present invention wherein R is a lower alkyl group, examples of R are methyl, ethyl, propyl, butyl, pentyl, hexyl and the branched chained isomers thereof. Examples of lower alkylamino and dilower alkylamino represented by R are methylamino, dimethylamino, ethylamino, diethylamino, methylethylamino, propylamino, dipropylamino, ethylpropylamino, butylamino, dibutylamino, propylbutylamino, pentylamino, dipentylamino, butylpentylamino, hexylamino, dihexylamino, etc.

The starting reactants for the preparation of the compounds of the present invention are 3-lower alkoxy-l6- hydroxymethylene l7 oxo-l,3,5(l0)-estratrienes. The reaction, generally, can be illustrated by the following equation, although there are exceptions as shown hereinafter.

n A: T0021 HR a H (1-H H2O wherein R and R are as defined hereinbefore.

3,091,609 Patented May 28, 1963 The compounds used as reagents and illustrated by HR above can be, for example, lower alkyl alkanols such as ethanol, methanol, propanol, etc. They can also be lower alkyl mercaptans, such as methyl mercaptan, ethyl mercaptan, propyl mercaptan, and butyl mercaptan. Other reagents such as potassium thioacetate, sodium thioacetate, thionyl chloride, etc. can be used as shown hereinafter in the examples. The present compounds can also be prepared using amines such as amomnia, methylarnine, dimethylarnine, methoxyamine, piperidine, cyclohexylamine, aniline, morpholine, piperazine, Z-aminopyridine, Z-dimethylaminoethylamine, 4-(2-pyridyl)-piperazine, or the like.

When a steroid starting compound such as a 3-lower alkoxy l6 hydroxymethylene-U-oxo-1,3,5(10)-estratrione is reacted with piperazine, the product obtained is a di-substituted piperazine in which R in the above formulas is an N-{3-lower alkoxy-l7-oxo-1,3,5(lO)-estratrienl6-ylidenemethyl]azapentamethyleneimino radical. In a similar manner, when a steroid starting compound such as described immediately above is reacted with, for example, potassium thioacetate the product obtained is a sulfide wherein R is a 3-lower alkoxy-l7-oxo-l,3,5( l0),16- ylidenemethylthio radical.

The foregoing condensations can generally be effected by heating at reflux for about 2 to 72 hours, usually 24- 28 hours, the 3-lower alkoxy-l6-hydroxymethylene-17- oxol,3,5(l0)-estratriene steroid starting compound with a small stoichiometric excess (ordinarily about 10%) of the lower alkyl alkanol, sulfur containing reagent or amine (as hereinabove defined) in a. solvent such as ethanol or benzene. When using certain of the reagents such as lower alkyl alkanols and lower alkyl mercaptans, it is advantageous to carry out the condensation in the presence of an acid catalyst such as para-toluene-sulfonic acid; with a halogen-introducing reagent such as thionyl chloride an excess of the reagent may serve as solvent.

The products may usually be isolated by concentrating the reaction mixture to the point where solids begin to appear, chilling and then separating the crude product by filtration. The crude products thus obtained may then be recrystallized from acetone-petroleum ether solution, methylene chloride-ether solution or the like.

The compounds of. this invention are estrogenic agents and may be used in estrogenic replacement therapy. They are also anti-cholesteremic agents and as such may be used to combate antherosclerosis. The compounds can be in such pharmaceutical forms as tablets, capsules, pills, etc. They can be combined with inert fillers, diluents, excipients and ingredients necessary in the preparation of pharmaceutical formulations. The ingredients can be treated to form long acting granules which in turn are tableted, encapsulated or otherwise prepared for ultimate pharmaceutical use.

The following examples illustrate in detail the preparation of specific compounds within the scope of the present invention.

EXAMPLES 1-12 Condensation of Amines With 16-Hydroxymelizylerzeestrone 3-Methyl Ether A solution or suspension of lfi-hydroxymethyleneestrone 3-methyl ether [3. C. Bardham, J. Chem. Soc., 1848 (1936)] in 35 cc. of absolute alcohol or benzene per 0.003 mole of steroid and a slight excess of amine is refiuxed for several hours. The solution shows a negative test with 1% ethanolic ferric chloride solution. Concentration or dilution with water precipitates the aminoethylene steroid. The product is collected and recrystallized. The products obtained by this general procedure are shown in Table I.

TABLE I Reaction Reaction Yield M.P., Anal. Product name Reagent (Ltime) solvent Recrystn. solvent percent C. [01]]; Cone. solvent ours (1) 16-pipericllnomethylene- Piperidine.-.. 22 Absolute al- Acetone-pet. her 96 183-186 184-186 +218 1.1% in CIIOl estrone methyl ether. cohol. (13.1. -70). (2) lfi-morpholinotnethyl- Morpholino--- 24 .d0 ..d0 94 195-198 198-200 +204 1.3% in 01101 oneestrone methyl ether. (3) lo-anilinomethylene- Aniline 48 de Acetone-whether 03 171-173 172-174 +47 0.6%111 (315101;.

estrone methyl ether. (4) 16-aminomethylene- Ammonia... 72 1101101101.. (l0 68 204-206 210-212 +95 0.9%111 CHC1 estrone methyl ether. (deo) (000.) (5) 16-N.N-diethylaznino- N,N-tlietl1yl 72 Absolute al- 84 +00 1.4% in CHCI ethylamino methyleneethylcnecoho]. estrone methyl ether. diamine. (6) IB-methylamlnemcthyl- Methylmnine. 48 Methanolun Ethanolmethylene 60 220-222 220-222 +111 08% in CHCh.

eneestrone methyl ether. chlorlde. (7) 16-(2-pyridylamino- 2-amine- 48 Absolute Acetone-pet. ether. 82 189-191 194-106 +53 0.7% in CIlCl methylene)estrone pyridine. alcohol. methyl ether (8) 16,16-(piperazin-1,4- Piperazine 20 Benzene Methylene 48 320 325 +207 0.6% in CHCh.

diyldimethylidyne) hydrate chloride-ether (deo) (doe) dlestronedimethyl other (e) 1s-[4-(2-pyridylJ-1- 1(2-pyr1dyl) 20 Abs lute 10 33 178-179 178-180 +188 0.9%111 01101;.

piperazlnyl methylene]- pipcrazino alcohol estrone methyl ether (10) IG-eyclohoxylamino- Gyelohexyla- 48 0 83 109-171 170-172 +03 0.5% in CHCI mfithyleneestrone methyl mine at or (11) lli-dlethylaminorneth- Diethyl- 22 do Ether-pct. ether 90 143-145 144-140 +184 0.7% in CIlClg.

yleneestrone methyl other amino (13.1. 60-70) (12) lfi-methoxyamino- Methoxy- 1 --do Acetone-pet. 0th!!! 70 133-136 145-147 +149 0.6% in CHCh.

methyleneestroue amine hy- (13.1. 60-70) methyl ether droehlorlde,

sodium acetate EXAMPLE 13 30 from ether-methanol gives white crystals, melting point e 25 a Preparation of 16,16-(Thiodtmethyhdyne)-D1estr0ne [MD +93 (1% m CHC13) Dzmethyllzther EXAMPLE 17 Y the general Procedure of Examines 1-12, Preparation of 16-15011utoxymethyleneestrone Methyl droxymethylencestrone 3-mcthyl ether 18 heated with po- 3 tassium thiolacctatc to give 16,l6'-(thiodimcthylidync)- diestrone dimethyl other, melting point 283-285 C.

(dcc.), 9 +184 0.5% in Cl-iCl EXAMPLE 14 Preparation of ]6-N,N-DiethyIaminoethylaminomethylene Estrone Methyl Ether Hydrochloride A solution of 700 mg. of 16-N,N-diethylaminoethylaminomcthyleneestrone methyl ether (Table 1, entry 5) in 20 cc. of other is treated with 10 cc. of ether saturated 45 with hydrogen chloride. Upon clarification of the milky solution by the addition of absolute alcohol, a crystalline product separates after chilling. Filtration gives 500 mg. (61%) of product, melting point 176-177 C. dec., +137 (0.8% in CHCl EXAMPLE 15 Preparation of I6-N,N-Diethylqminoethylaminomethylene Estrone Methyl Ether Melhiodz'de A suspension of 1 g. of l6-N,N-dicthylaminocthylaminomethyleneestronc methyl ether in 5 cc. of methyl iodide is warmed on the steam bath with swirling for approximately 5 minutes. The solution is evaporated to dryness under reduced pressure and the residue is recrystallized from methanol-ether to give 875 mg. (65%) of product as a methanolatc, melting point 156l60 C. (gas). Three recrystallizations from absolute alcohol-ether gives white crystals, melting point 223-225" C., +66 (0.5% in CHCl EXAMPLE 16 65 Preparation of 16-Chloromethyleneestrone Methyl Ether A solution of l g. of l6-hydroxymcthyleneestronc methyl ether and 3 cc. of thionyl chloride is allowed to stand at room temperature for minutes. The resulting 70 red solution is poured into an ice cold 10% sodium hydroxide solution (200 cc.) with stirring. After 30 minutes the solid collected by filtration and recrystallized from benzene-methanol to give 760 mg. (72%) of product, melting point 134-135 C. Two recrystallizations A suspension of 1 g. of 16-hydroxyrncthylcneestrone methyl ether, mg. of p-toluenesulfonic acid and 3 cc. of isobutyl alcohol in 30 cc. of reagent benzene is refluxed for 18 hours, solution being complete at the boiling point. The water formed is removed by means of a Dean-Stark distilling receiver. The cooled solution is washed with saturated sodium bicarbonate solution, water, dried with anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The resulting solid is triturated with petroleum ether (boiling point 60 C.) and collected to give 838 mg. (71%) of product in two crops, melting point 123-127 C. Recrystallization from petroleum ether gives white crystals, melting point l26-l28 C., [M +96 (2.3% in CHCl EXAMPLE 1 8 Preparation of I 6 -n-Propylthiomethy leneestrone Methyl Ether We claim: 1. A compound of the formula:

0 I lit c-n 6 wherein R is lower alkyl and R is a nadical selected from 4. The compound lfi-chloromethyleneestrone methyl the group consisting of lower alkylthio, isobutoxy, haloether. gen, 3-lower =alkoxy-17-oxo-1,3,5(10)-estrariene 16- 5. The compound l6-isobutoxymethyleneestrone methyl ylidenemethylthio and N[3-1ower .a1koxy-17-oxo 1,3,5 fi (10)-estratrien 16 ylidenemethyl]azopentamethylenei- 5 The comlwund 16-n-pl'opylthlomethyleneeStfOne mino radicals. y ether- 2. The compound 16,16 -(\thwmethyhdyne)-d1estrone References cited in the file of this patent dimethylether.

3. The compound 16,16'-(piperazin-1,4-diyldimethyl- UNITED STATES PATENTS idyn e)-diestrone dimethyl ether. 10 3,030,357 Clinton Apr. 17, 1962 

1. A COMPOUND OF THE FORMULA: 